Bruton's tyrosine kinase (abbreviated Btk or BTK) also known as tyrosine-protein kinase BTK is an enzyme that in humans is encoded by the BTK gene. BTK was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952. BTK is a kinase that plays a crucial role in B-cell development. Its exact mechanism of action remains unknown, but it plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor. Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C, which in turn hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.
Ibrutinib (PCI-32765), the first selective BTK inhibitor, was approved by the US FDA in November 2013 for the treatment of mantle cell lymphoma and in February 2014 for the treatment of chronic lymphocytic leukemia.
Celgene (following its acquisition of Avila) is developing spebrutinib (CC-292, AVL-292, structure shown), the lead from a series of Bruton's tyrosine kinase (Btk) inhibitors, including CNX-652, for the potential oral treatment of B-cell cancers such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), B-cell mediated autoimmune diseases such as rheumatoid arthritis (RA) and multiple myeloma. In October 2013, a phase II RA trial began. In June 2011, a phase Ib trial in B-cell cancers was initiated; in February 2013, a phase I trial in CLL/small lymphocytic leukemia (SLL) began. In December 2013, a phase I trial was initiated in DCBCL patients in the US, France and Italy. In January 2014, initial data from a phase I/II study of spebrutinib in combination with lenalidomide in CLL patients were expected in 2014.
CC-292 is described chemically as N-(3-(5-fluoro-2-(4-(2-methoxyethoxyl)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide, and has the structural formula shown as Formula 1:

Patent application publication No. US2010029610A1 disclose preparation method of CC-292 and closely related analogues. The synthetic route of CC-292 is shown below.

In the first step of US2010029610A1, it's easy to produce 2-substituted and 2,4-bis substituted products with low yield and difficult to separate.